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Meeting abstract

In 2012, recommended therapies for SLE include antimalarials, glucocorticoids, azathioprine,
mycophenolate mofetil (or myfortic acid), cyclophosphamide, and other immunosuppressants.
Belimumab has been added recently. Most are targeted toward adaptive immune responses.
We now suspect that several pathways in innate immunity are also critical to driving
SLE, including dendritic cells (major source of IFNα), and monocyte/macrophages that
appear central in the damage that occurs to renal tissue in lupus nephritis. Abnormalities
in neutrophils may also drive IFNα production and damage to endothelial cells. Therefore,
treatments that modify these innate immune cells are of great interest. Antimalarials
primarily suppress antigen-presenting cells (APC), including TLR activation; clinically
they suppress disease activity and damage, but not strongly. Glucocorticoids suppress
DC, monocytes and lymphocytes, with reduction of trafficking of proinflammatory cells
to target tissues, but they are quite toxic. Belimumab is directed primarily at prevention
of B-cell maturation and has clinical benefits that are not large when added to standard
therapies.

Among the potential new therapies that influence APC is Laquinimod, a quinoline derivative
administered orally, which has recently been shown to reduce the number of new MRI
lesions and disability in patients with multiple sclerosis. A recent study in murine
EAE shows that Laquinimod suppresses activity of DC, and prevents monocyte/macrophages
from accessing the CNS. The suppressed APC functions result in reduced number of effector
T cells (Th1, Th17) in target tissue. In addition, Laquinimod induces regulatory T
cells and myeloid regulatory CD16+LyC6+ cells that on adoptive transfer suppress clinical disease. We have recent data, submitted
for the 2012 ACR meeting, showing similar immune alterations in a murine model of
lupus nephritis, including dramatic benefits on protection of young mice from clinical
disease, and regression of disease in mice started on treatment after developing heavy
proteinuria. Renal damage is minimal.

Downregulation of innate immune cells to minimize their activation of adaptive immunity,
and their ability to invade and initiate damage target tissues should result in not
only less active acute disease but also less future damage. This approach might be
discussed at the Whistler meeting.

Acknowledgements

The Laqinimod experiments in murine lupus were supported by Teva Pharmaceuticals,
Ltd.